N-arachidonoyl glycine

Lipidomics Gateway (22 July 2009) [doi:10.1038/lipidmaps.2009.19]

Lipoamino acids have emerged from the identification of obscure prokaryotic molecules, through pharmacologically active synthetic compounds, to endogenous mammalian signaling molecules. N-arachidonoyl glycine (NAGly), the best-characterized acyl amino acid, has pain-relieving properties.

The earliest reports on lipoamino acids – amino acids conjugated with fatty acid molecules – described compounds of bacterial origin with complex fatty acid moieties and obscure functions. Simpler forms of these compounds contain one fatty acid and one amino acid linked by an amide bond, and are termed acyl amino acids. Forming part of the N-acyl amide sub-class of fatty acyls, the characterization of these molecules is proceeding apace.

NAGly synthesis: Second-guessing nature

Model of N-arachidonoyl glycine. Visit NAGly in the LIPID MAPS database for more molecular information.

The endocannabinoid anandamide (N-arachidonoyl ethanolamine, AEA) activates cannabinoid receptors with downstream signaling effects. NAGly was first investigated as a synthetic compound related to AEA; the two molecules differ in just one extra oxidation of NAGly ¹ . Nevertheless, this difference greatly reduces the ability of NAGly to activate the two cannabinoid receptors. Despite this seeming lack of potency, pain-relieving and anti-inflammatory effects of NAGly have been identified in rodents ^{2 3} and in 2001 its endogenous occurrence was discovered ⁴ . In the central nervous system of rats, levels of NAGly are greater than those of anandamide, and it also occurs in several hematopoietic cell lines and other mammalian tissues.

Signaling effects: Receptors needed

If it is not a cannabinoid receptor agonist, how does NAGly elicit biological responses? Several potential routes have been identified, including activation of the orphan G protein receptor GPR18 ⁵ , inhibitory interaction with the glycine transporter GLYT2a ⁶ and inhibition of AEA hydrolysis by fatty acid amide hydrolase (FAAH) ⁷ . NAGly is also a substrate for cyclooxygenase 2, producing amino acid conjugates of prostaglandins ⁸ . It has been suggested that NAGly effects may derive from increasing the concentration of AEA, or from modulating the ratio of prostaglandins from the pro-inflammatory PGE2 towards the inflammation-resolving J prostaglandins ⁹ .

Family: Precursors, relations and implications

Endogenous NAGly appears to be derived from AEA by two pathways; arachidonic acid, released from AEA by FAAH activity, can be conjugated with glycine, probably in an enzyme complex that includes the FAAH; alternatively sequential oxidative metabolism of anandamide catalysed by an alcohol dehydrogenase gives rise to NAGly via an N-arachidonoyl glycinal intermediate ^{1 10} . Not all activity of AEA can be attributed to cannabinoid receptor activation and hence the conversion of AEA into NAGly, with activation of NAGly receptors, may account for the additional responses. Further work is needed to characterize the physiological roles of NAGly and of the wider family of acyl amino acids. This family has just been extended (see our research highlight "Targeted lipidomics: Planned discovery") raising the possibility that many more functions for this sub class of lipids are waiting to be found.